Despite the widespread appreciation that the medial temporal lobe (MTL) is necessary for episodic associative memory formation and retrieval, there is a fundamental gap in understanding the post-encoding processes by which memories are consolidate, or stabilized. This gap in knowledge is a critical problem because a host of psychiatric and neurologic disorders stem from a primary dysfunction of the MTL and how it contributes to associative memory. The long-term goal is to understand the mechanisms that support memory consolidation and what consequences these changes have on the integration of our new memories with past experience. The objective of the current proposal is to test a model of how post-encoding reactivation within MTL substructures known to be involved in encoding different aspects of an experience relate to the consolidation of those experiences. The central aim of the project is to establish reactivation as a mechanism for human episodic memory consolidation and to reveal distinct patterns of reactivation related to distinct kinds of memories. The rationale for the proposed research is that a better understanding of how the memories become stabilized over time will lead to a strong theoretical framework within which strategies for the understanding of mental disease disrupting memory will develop. The objective will be to identify, modulate and look for long-term consequences of reactivation which will be accomplished by pursuing three specific aims: 1) identify post-encoding patterns of reactivation that characterize recent prior experiences and relate to later associative memory for memories of different content; 2) modulate post-encoding reactivation by linking reactivation with the amount of prior learning and hippocampal activity; and 3) linking post-encoding reactivation with longer-term changes in the memory representations. Strong preliminary data demonstrate the feasibility of project aims in the applicant's hands. Under aim 1, evidence for reactivation of specific encoding experiences has been identified within the human hippocampus and evidence for distinct MTL interactions following encoding tasks presenting different memoranda. Under aim 2, preliminary data provide evidence that the magnitude of hippocampal activation during encoding correlates with post-encoding hippocampal-cortical interactions. Under aim 3, preliminary data identify expected patterns of change in the network representation of associative memories during reactivation that relate to behavioral measures of associative memory strength thus providing a much needed link between memory consolidation changes in the brain and strengthening of memories behaviorally. The approach is innovative and significant because we know very little about how interactions between MTL regions contribute to memory consolidation; it is highly programmatic because it is directly-motivated from our prior work on the role of MTL subregions to memory encoding and uses novel approaches to studying consolidation by looking for patterns of reactivation during post-encoding rest. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because advancement in our understanding of the mechanisms by which memories consolidate in the normal brain is necessary to illuminate the mechanisms that could go awry in diseases that compromise the medial temporal lobes such as Alzheimer's disease. Specifically, the proposed research is relevant to NIH's mission because is expected to advance translational knowledge by providing empirical support in humans for processes identified in animals models and, thus, to strengthen theories of memory consolidation within which clinical researchers can develop strategies for the diagnosis and treatment of psychiatric and neurologic disorders.